PROJECT SUMMARY_PROJECT 1 Resilience to aging-related challenges can be the difference between physical and mental decline and a longer, healthier life. The increased prevalence of sleep disturbances, mood alterations and cognitive impairment observed in the elderly population can have substantial effects on quality of life and overall health. Traditional medicine systems have identified numerous botanicals that support health in older adults. Many of these botanicals have compelling preclinical evidence supporting their potential efficacy in humans yet few have been evaluated in well-designed clinical trials. This is due in part to a failure of these preclinical studies to focus on translationally relevant endpoints and biomarkers of efficacy. This project proposes to establish the experimental framework necessary to evaluate a botanical agent with promising in vitro mechanistic results in a mammalian system, in order to generate the data necessary to inform a well-designed clinical trial. This proposal will focus on the resilience-promoting effects of the plant Centella asiatica (L.) Urban. This herb is used in Ayurvedic and traditional Chinese medicine as a nerve tonic and to improve cognitive function. Our lab and others have shown that low doses of the water extract of Centella asiatica (CAW) can improve cognitive function in rodent models of aging and Alzheimer?s disease. Anxiolytic effects and improvement in insomnia as a result of administering the extract have also been reported. However, few clinical trials have attempted to validate these effects and each has suffered from severe methodological flaws such as lack of controls, being underpowered and assessing appropriate biomarkers of efficacy. In this study we will address critical knowledge gaps hindering the clinical development of CAW including proper dosage, optimal product formulation and identification of translational biomarkers. Using aged mice we will explore the effects of a range of CAW doses on cognitive impairment, sleep and resilience to sleep deprivation, and anxiety and depression. Brain imaging, sleep phenotype, as well as circulating hormone levels and blood DNA methylation patterns will all be evaluated as biomarkers for target engagement. We will also determine the effects of constituent compounds from the CAW extract on the same behavioral endpoints in order to inform product formulation to be used in a clinical trial. These experiments will determine the efficacy of CAW as a botanical agent to promote functional resilience to age-related challenges and thereby facilitate its translation to a clinical trial in older adults. Additionally, this study will establish a methodological platform that can be used in future studies with any promising botanical to provide the necessary in vivo testing to move towards clinical testing.